US4725689A - Preparation of 2-amino-3-cyano-5-dialkoxymethylpyrazines and intermediates for this method - Google Patents
Preparation of 2-amino-3-cyano-5-dialkoxymethylpyrazines and intermediates for this method Download PDFInfo
- Publication number
- US4725689A US4725689A US06/776,462 US77646285A US4725689A US 4725689 A US4725689 A US 4725689A US 77646285 A US77646285 A US 77646285A US 4725689 A US4725689 A US 4725689A
- Authority
- US
- United States
- Prior art keywords
- cyano
- amino
- phthalimidopyrazine
- preparation
- dichloromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a process for the preparation of 2-amino-3-cyano-5-dialkoxymethylpyrazine derivatives, and 2-aminopyrazine derivatives substituted in the 3- and 5-positions, of the general formula I ##STR6## where R 1 and R 2 are each hydrogen or a protective group usually employed for amino groups, and may furthermore be bonded to one another, R 3 is --CH 2 --O--CO--CH 3 (a), --CH 2 OH (b), ##STR7## or --C.tbd.N (d), and R 4 is --CHCl 2 or --CHBr 2 , or, where R 1 and R 2 are each a protective group, R 4 is ##STR8## as novel intermediates for this process.
- the general object of the invention was to make the physiologically important compound folic acid ##STR9## and its derivatives more readily accessible.
- the present invention therefore relates not only to the novel intermediates of the general formula I and in particular those of the general formula II, but also to a process for the preparation of 2-amino-3-cyano-5-dialkoxymethylpyrazine derivatives of the general formula III ##STR13## where R 1 and R 2 are each hydrogen or a protective group usually employed for amino groups, and may furthermore be bonded to one another, and R 5 and R 6 are each alkyl of 1 to 4 carbon atoms, or R 5 and R 6 together form an ethylene or propylene radical which is unsubstituted or substituted by methyl, wherein
- novel starting materials of the general formula IV can be prepared in relatively good yields by a process for which patent protection has been applied at the same time (cf. Patent Application No. P 34 33 959.0--O.Z. 0050/37335), by halogenation of the corresponding 2-amino-3,5-dimethylpyrazines, which in turn can advantageously be obtained by, for example, cyclization of ⁇ -iminodipropionitrile of the formula V ##STR20## with a hydrogen halide.
- ⁇ -Iminodipropionitrile can be obtained by, for example, subjecting ammonia, acetaldehyde and hydrocyanic acid to the reaction described in German Laid-Open Application No. DOS 1,493,752.
- the mixture of halogenation products obtained in the stated processes contains the desired isomer in an amount of from 60 to 70% when the process is carried out appropriately, and can be used as such.
- Conversion of the compounds of the formula IV to the corresponding 3-hydroxymethyl compounds Ib can be carried out in one step or via the novel 3-acetoxy compounds Ia.
- the compounds IV are dissolved in a polar organic solvent, such as dimethylformamide or, in particular, dimethyl sulfoxide, and reacted with an alkali metal acetate in the presence of glacial acetic acid under mild conditions, for example with prolonged stirring at room temperature, the product being obtained in good yield.
- the resulting product can be isolated and purified in a conventional manner without difficulty and can then be converted to the corresponding 3-hydroxymethyl compounds Ib in a transesterification reaction with a low-boiling alcohol, such as methanol, in the presence of an acidic catalyst, such as p-toluene-sulfonic acid, the methyl acetate formed being distilled off.
- a low-boiling alcohol such as methanol
- an acidic catalyst such as p-toluene-sulfonic acid
- the methyl acetate formed being distilled off.
- water for example in an amount of from 3 to 20%, advantageously about 5%, based on the reaction mixture, is added to the reaction mixture described, which consists of IV, the solvent, glacial acetic acid and the alkali metal acetate, the 3-hydroxymethyl compound Ib is obtained directly under otherwise very similar conditions, the yield of the product after recrystallization being about 50%.
- the alcohol thus obtained can be isolated in a convenient and conventional manner,
- Oxidation of the 3-hydroxymethyl compounds Ib to the novel 3-formyl compounds Ic must be carried out using an oxidizing agent which exclusively oxidizes the hydroxymethyl group to the formyl group, in a solvent which is insensitive to this oxidizing agent.
- the reaction takes place surprisingly advantageously with agents which effect oxidation under mild conditions, eg. pyridinium chlorochromate in a halohydrocarbon such as dichloromethane as a solvent. This method of oxidation is described in more detail in Tetrahedron Letters 1975, 2647.
- the conversion of the 3-formyl compounds Ic to the corresponding 3-cyano compounds Id is carried out in a conventional manner, so that a detailed description of the process is unnecessary.
- the reaction takes place particularly simply and without difficulty when Ic in a polar solvent, such as dimethyl sulfoxide, is first reacted with a hydroxylammonium salt, the oximino group is esterified with a conventional acylating agent, such as acetic anhydride, and the acetoximino-containing compound is then subjected to thermal decomposition in a fairly high-boiling solvent. This reaction too gives surprisingly good yields.
Abstract
Description
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19843433960 DE3433960A1 (en) | 1984-09-15 | 1984-09-15 | METHOD FOR PRODUCING 2-AMINO-3-CYANO-5-DIALKOXYMEHTYL-PYRAZINES AND INTERMEDIATE PRODUCTS FOR THIS METHOD |
DE3433960 | 1984-09-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
US4725689A true US4725689A (en) | 1988-02-16 |
Family
ID=6245512
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/776,462 Expired - Fee Related US4725689A (en) | 1984-09-15 | 1985-09-16 | Preparation of 2-amino-3-cyano-5-dialkoxymethylpyrazines and intermediates for this method |
Country Status (4)
Country | Link |
---|---|
US (1) | US4725689A (en) |
EP (1) | EP0175264B1 (en) |
JP (1) | JPS6172766A (en) |
DE (2) | DE3433960A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1493752A1 (en) * | 1965-11-16 | 1969-11-20 | Bayer Ag | Process for the preparation of pure anhydrous 2-amino-propionitrile |
US4267327A (en) * | 1978-03-23 | 1981-05-12 | Farmitalia Carlo Erba S.P.A. | 2-Hydroxymethyl-pyrazine derivatives and process for their preparation |
-
1984
- 1984-09-15 DE DE19843433960 patent/DE3433960A1/en not_active Withdrawn
-
1985
- 1985-09-10 EP EP85111443A patent/EP0175264B1/en not_active Expired
- 1985-09-10 DE DE8585111443T patent/DE3574255D1/en not_active Expired
- 1985-09-11 JP JP60199635A patent/JPS6172766A/en active Pending
- 1985-09-16 US US06/776,462 patent/US4725689A/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1493752A1 (en) * | 1965-11-16 | 1969-11-20 | Bayer Ag | Process for the preparation of pure anhydrous 2-amino-propionitrile |
US4267327A (en) * | 1978-03-23 | 1981-05-12 | Farmitalia Carlo Erba S.P.A. | 2-Hydroxymethyl-pyrazine derivatives and process for their preparation |
Non-Patent Citations (5)
Title |
---|
E. C. Taylor et al, J. Org. Chem. 45, 1980, pp. 2485 to 2489. * |
E. C. Taylor et al, J. Org. Chem. 46, 1981, pp. 1394 to 1402. * |
E. C. Taylor et al, J. Org. Chem., vol. 43, No. 4, 1978, p. 736. * |
E. J. Corey et al, Tetrahedron Letters, No. 31, pp. 2647 to 2650. * |
Georg Thieme Verlag, Stuttgart, 1962, pp. 728, 731, 748. * |
Also Published As
Publication number | Publication date |
---|---|
EP0175264A3 (en) | 1987-01-28 |
EP0175264A2 (en) | 1986-03-26 |
JPS6172766A (en) | 1986-04-14 |
DE3574255D1 (en) | 1989-12-21 |
EP0175264B1 (en) | 1989-11-15 |
DE3433960A1 (en) | 1986-03-27 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BASF AKTIENGESELLSCHAFT, 6700 LUDWIGSHAFEN, RHEINL Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:LEININGER, HARTMUT;LITTMANN, WOLFGANG;PAUST, JOACHIM;REEL/FRAME:004777/0586 Effective date: 19850911 Owner name: BASF AKTIENGESELLSCHAFT,GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LEININGER, HARTMUT;LITTMANN, WOLFGANG;PAUST, JOACHIM;REEL/FRAME:004777/0586 Effective date: 19850911 |
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Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
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FPAY | Fee payment |
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FPAY | Fee payment |
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REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20000216 |
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STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |